This is an exploratory study to provide preliminary data to support a future R01 application. This pilot study addresses the question of whether past and present environmental arsenic exposure act together with UV exposure to impact risk of melanoma in the New Mexico non-Hispanic white population. New Mexico ranks third among all US states for melanoma incidence in non-Hispanic whites in 2002-2006. Primary skin cells exposed to biologically plausible low concentrations of arsenic show down-regulation of specific DNA repair and cell cycle checkpoint genes considered significant in development and progression of melanoma. Our hypothesis is that arsenic acts as a co-carcinogen with UV exposure in development of malignant melanoma skin cancer in this population by both inhibiting repair of UV-induced DNA damage and increasing intramelanocyte oxidative stress. This pilot study employs a novel in vivo-in vitro approach to directly address this hypothesis: DNA damage and repair inhibition of UV damage in the presence of arsenic will be determined in primary human melanocytes in vitro;arsenic exposure concentrations relevant to estimated blood arsenic concentrations in exposed humans will be used. In parallel, the association between arsenic drinking water levels and in vivo DNA repair capacity in melanoma and non-melanoma patients will be evaluated controlling for UV exposure and serum vitamin D levels. While ingestion of drinking water containing high concentrations of environmental inorganic arsenic is a known risk factor for non-melanoma skin cancer, a significant positive association between body arsenic (toenail) levels and melanoma skin cancer risk has been shown in a (predominantly) Caucasian U.S. population. The present pilot study explores and extends those results. New Mexico provides a unique opportunity for conduct of this exploratory study since melanoma rates are high in non-Hispanic Caucasian populations, arsenic is relatively high in the state and UV levels are high due to low latitude and high elevation across much of the state. Understanding the mode of action by which arsenic may increase the risk of developing melanoma in the non-Hispanic white population and the range of drinking water exposure concentrations at which these events may occur may significantly improve development of coherent public health prevention strategies. PUBLIC HEALTH RELEVANCE: Melanoma incidence and deaths in the U.S. continue to rise with a current annual incidence of 60,000 new cases and 8,000 deaths. Recently a significant positive association between body arsenic (toenail) levels and melanoma skin cancer risk was shown in a (predominantly) Caucasian U.S. population. We here apply a novel approach to address arsenic exposure as a modifiable co-carcinogenic risk factor that may interplay with UV to increase the incidence of melanoma. Our hypothesis is that arsenic acts as a co-carcinogen with UV exposure in development of malignant melanoma skin cancer in the human population by both inhibiting repair of UV-induced DNA damage and increasing intramelanocyte oxidative stress. This study will provide crucial data addressing mechanisms by which arsenic can cause DNA damage and inhibit repair of UV- induced DNA damage in in vitro studies in melanocytes and in melanoma patients compared with non- melanoma patients exposed to similar environmental arsenic levels. New Mexico provides a unique opportunity for conduct of this exploratory study since melanoma rates are high in fair-skinned populations and both arsenic and UV levels are relatively high across much of the state. Understanding mechanisms by which arsenic may increase the risk of developing melanoma and the range of drinking water exposure concentrations at which these events may occur has substantial public health significance in that it would greatly improve development of coherent prevention strategies.